Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA.
Division of Infectious Diseases, Department of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA.
Sci Rep. 2024 Aug 6;14(1):18187. doi: 10.1038/s41598-024-69087-y.
Cryptococcus neoformans (Cn) is an opportunistic yeast that causes meningoencephalitis in immunocompromised individuals. Calorie restriction (CR) prolongs Cn replicative lifespan (RLS) and mimics low-glucose environments in which Cn resides during infection. The effects of CR-mediated stress can differ among strains and have only been studied in MATα cells. Cn replicates sexually, generating two mating types, MATα and MATa. MATα strains are more dominant in clinical and environmental isolates. We sought to compare the effects of CR stress and longevity regulation between congenic MATα and MATa. Although MATα and MATa cells extended their RLS in response to CR, they engaged different pathways. The sirtuins were upregulated in MATα cells under CR, but not in MATa cells. RLS extension was SIR2-dependent in KN99α, but not in KN99a. The TOR nutrient-sensing pathway was downregulated in MATa strains under CR, while MATα strains demonstrated no difference. Lower oxidative stress and higher ATP production were observed in KN99α cells, possibly due to higher SOD expression. SIR2 was important for mitochondrial morphology and function in both mating types. Increased ATP production during CR powered the upregulated ABC transporters, increasing efflux in MATα cells. This led to enhanced fluconazole tolerance, while MATa cells remained sensitive to fluconazole. Our investigation highlights differences in the response of the mating types to CR.
新生隐球菌（Cn）是一种机会性酵母，可引起免疫功能低下个体的脑膜脑炎。热量限制（CR）可延长 Cn 的复制寿命（RLS），并模拟感染期间 Cn 所处的低糖环境。CR 介导的应激的影响在不同菌株之间可能不同，并且仅在 MATα 细胞中进行了研究。Cn 通过有性繁殖产生两种交配型，MATα 和 MATa。MATα 菌株在临床和环境分离株中更为优势。我们试图比较同源 MATα 和 MATa 菌株之间 CR 应激和寿命调节的影响。尽管 MATα 和 MATa 细胞通过 CR 延长了它们的 RLS，但它们采用了不同的途径。在 CR 下，sirtuins 在 MATα 细胞中上调，但在 MATa 细胞中没有上调。在 KN99α 中，RLS 延长依赖于 SIR2，但在 KN99a 中则不然。TOR 营养感应途径在 CR 下下调，而 MATα 菌株则没有差异。在 KN99α 细胞中观察到较低的氧化应激和更高的 ATP 产生，这可能是由于更高的 SOD 表达所致。SIR2 对于两种交配型的线粒体形态和功能都很重要。在 CR 期间增加的 ATP 产生为上调的 ABC 转运蛋白提供动力，从而增加了 MATα 细胞的外排。这导致了对氟康唑的耐受性增强，而 MATa 细胞对氟康唑仍然敏感。我们的研究强调了交配型对 CR 反应的差异。
